Asymmetric ‘Clip-Cycle’ Synthesis of Pyrrolidines and Spiropyrrolidines

TY - JOUR

T1 - Asymmetric ‘Clip-Cycle’ Synthesis of Pyrrolidines and Spiropyrrolidines

AU - Clarke, Paul Andrew

AU - Ermanis, Kristaps

AU - Maddocks, Christopher

N1 - © 2020 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2020/10/16

Y1 - 2020/10/16

N2 - The development of an asymmetric ‘clip-cycle’ synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by ‘clipping’ them to thioacrylate via an al-kene metathesis reaction. Enantioselective intramolecular aza-Michael cyclisation onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reac-tion accommodated a range of substitution to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ke-tone and oxoester-containing substrates. DFT studies sup-ported the aza-Michael cyclisation as the rate and stereo-chemical determining step, and correctly predicted the for-mation of the major enantiomer. The catalytic asymmetric syntheses of N-methyl pyrrolidine alkaloids (R)-irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties were achieved using the ‘clip-cycle’ methodology.

AB - The development of an asymmetric ‘clip-cycle’ synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by ‘clipping’ them to thioacrylate via an al-kene metathesis reaction. Enantioselective intramolecular aza-Michael cyclisation onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reac-tion accommodated a range of substitution to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ke-tone and oxoester-containing substrates. DFT studies sup-ported the aza-Michael cyclisation as the rate and stereo-chemical determining step, and correctly predicted the for-mation of the major enantiomer. The catalytic asymmetric syntheses of N-methyl pyrrolidine alkaloids (R)-irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties were achieved using the ‘clip-cycle’ methodology.

U2 - 10.1021/acs.orglett.0c03090

DO - 10.1021/acs.orglett.0c03090

M3 - Article

SN - 1523-7060

VL - 22

SP - 8116

EP - 8121

JO - Organic Letters

JF - Organic Letters

ER -